Many cancers are believed to result from a series of genetic alterations leading to progressive disordering of normal cellular growth mechanisms (Nowell (1976) Science 194:23, Foulds (1958) J. Chronic Dis. 8:2). The deletion or multiplication of copies of whole chromosomes or chromosomal segments, or specific regions of the genome are common (see, e.g., Smith et al. (1999) Breast Cancer Res. Treat., 18: Suppl. 1: 5–14; van de Vijer & Nusse (1991) Biochim. Biophys. Acta. 1072: 33–50; Sato et al. (1990) Cancer. Res., 50: 7184–7189). In particular, the amplification and deletion of DNA sequences containing proto-oncogenes and tumor-suppressor genes, respectively, are frequently characteristic of tumorigenesis. Dutrillaux, et al.(1990) Cancer Genet. Cytogenet., 49: 203–217. As an example, overexpression of the HER2/neu (c-erbB-2) proto-oncogene product is found in approximately 20–30% of primary breast cancers and in a similar fraction of human gastric, ovarian, and lung carcinomas. For many of these malignancies, this overexpressed membrane growth factor receptor (p185HER2) is associated with HER2 gene amplification, more aggressive tumor growth, and reduced patient survival. Maguire & Greene (1989) Semin. Oncol. 16: 148–155; Singleton & Strickler (1992) Pathol. Annu 1: 165–190; Tripathy & Benz (1993) in Oncogenes and Tumor Suppressor Genes in Human Malignancies (Benz and Liu, eds.) pp. 15–60, Kluwer, Boston. In approximately 10–20% of HER2-overexpressing breast tumors, some gastric, and virtually all HER2-positive lung cancers, HER2-m RNA and protein overexpression occur in the absence of increased gene copy number, suggesting that HER2 transcriptional dysregulation may be a fundamental defect of clinical significance in these malignancies. Berger et al. (1988) Cancer Res. 48: 1238–1243; Kameda et al. (1990) Cancer Res. 50: 8002–8009; Kern et al. (1990) Cancer Res. 50: 5184–5191; King et al. (1989) Cancer Res. 49: 4185–4191; Slamon et al. (1989) Science 244: 707–712; Tandon et al. (1989) J. Clin. Oncol. 7: 1120–1128. It has been speculated that a primary defect leading to dysregulated HER2 transcription might also predispose to the in vivo development of gene amplification and stable acquisition of a more malignant tumor cell phenotype. Kameda et al., supra.; King et al., supra.; Hynes et al. (1989) J. Biol. Chem. 39: 167–173; Kraus et al. (1987) EMBO J. 6: 605–610; Pasleau et al. (1993) Oncogene 8: 849–854.
Recently, a previously unrecognized response element similar to those recognized by the ets transcriptional regulator family was identified within both the human HER2 and murine neu promoters. Scott et al. (1994) J. Biol. Chem. 269: 19848–19858. The ets multigene family of transcriptional regulators includes more than thirty known members that are involved in early embryonic development and late tissue maturation, directing stage-specific and tissue-restricted programs of gene expression. The ETS transcription factors, which are recognizable primarily by their 85 amino acid ETS DNA-binding domain, are dispersed across all metazoan lineages into distinct subfamilies. Ets genes can produce malignancies in humans and other vertebrates when overexpressed or rearranged into chimeras retaining the ETS domain. However, the particular ets gene family member responsible for HER2/neu-mediated cancers and other related cancers was not known prior to this invention.
Because most, if not all, cancers involve dysregulation of gene expression, a need exists for information as to transcription factors and other regulatory moieties that are involved in mediating the dysregulation. Such knowledge is helpful in developing methods and compositions for use in diagnosing and treating cancers. The present invention fulfills this and other needs.